Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage

Berg, Pablo J. E. J. van de; Yong, S. L.; Remmerswaal, Ester B. M.; Lier, R. A. W. Van; Berge, Ineke J. M. ten

doi:10.1128/cvi.00011-12

Cited by 84 publications

(67 citation statements)

References 40 publications

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“…In particular, the expansion of unusual T lymphocytes in peripheral blood (CD4 + CD28 − T cells) is strongly associated with the recurrence of acute coronary events42 and appears in other diseases,43 such as acute ischemic stroke 44. In contrast, accumulation of intermediately and late‐differentiated CD8 Tem cells in blood is associated with CMV infection 45, 46, 47…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

Nikitskaya

Lebedeva

Ivanova

et al. 2016

JAHA

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BackgroundAlthough an association between human herpesvirus (HHV) infection and atherosclerosis has been suggested, the data supporting such an association are controversial and, in most cases, are based on serological evidence or on the presence of cell‐associated HHV DNA, which do not report about actual viral replication. We quantified the DNA of all 8 types of HHVs in plasma, in which their presence is evidence of viral replication.Methods and ResultsUsing quantitative real‐time polymerase chain reaction, we evaluated the presence of HHV DNA in blood samples obtained at the time of hospitalization from 71 patients with acute coronary syndrome, 26 patients with stable coronary artery disease, and 53 healthy volunteers and in atherosclerotic plaques of 22 patients with peripheral artery disease who underwent endarterectomy. HHV‐5 (cytomegalovirus [CMV]) was the only HHV with a level that was higher in acute coronary syndrome patients than in the control group and that correlated with the level of high‐sensitivity C‐reactive protein. The numbers of effector memory T cells positively correlated with the numbers of CMV genome copies in carotid arteries plaques, whereas the numbers of central memory T cells negatively correlated with CMV copy numbers.ConclusionsOf all HHV levels, only CMV was higher in patients with stable coronary artery disease and acute coronary syndrome than in the healthy group, and its load correlated with the level of high‐sensitivity C‐reactive protein. The level of CMV in atherosclerotic plaques correlated with the state of immunoactivation of lymphocytes in plaques, suggesting that the reactivation of CMV may contribute to the immune activation associated with the progression of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

Nikitskaya

Lebedeva

Ivanova

et al. 2016

JAHA

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“…Production of pro-inflammatory cytokines in turn activates p38 in T cells, inhibits T cell telomerase activity, and promotes loss of CD28 and T cell differentiation, further creating a vicious cycle of immunosenescence (Macaulay et al 2013). CMVspecific T cells are found to express high levels of CX3CR1, which binds to injuried vascular endothelium-expressing fractalkine, and the β2-adrenergic receptor, which permits rapid response toward stress (Pachnio et al 2016;van de Berg et al 2012). It is important to note that not all persistent virus infections result in terminally differentiated T cells.…”

Section: And Atherosclerotic Cardiovascular Complicationsmentioning

confidence: 99%

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

2017

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Cytomegalovirus (CMV) is an important pathogen for both clinical and population settings. There is a growing body of research implicating CMV in multiple health outcomes across the life course. At the same time, there is mounting evidence that individuals living in poverty are more likely to be exposed to CMV and more likely to experience many of the chronic conditions for which CMV has been implicated. Further research on the causal role of CMV for health and wellbeing is needed. However, the strong evidence implicating CMV in type 2 diabetes, autoimmunity, cancer, cardiovascular disease, vaccination, and age-related alterations in immune function warrants clinical and public health action. This imperative is even higher among individuals living in socioeconomically disadvantaged settings and those exposed to high levels of chronic psychosocial stress.

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“…Finally, we evaluated the expression of homing receptors CCR7 (homing to LN), CCR5, CXCR3 (homing to a wide array of infected tissues) (22)(23)(24)(25)(26)(27)(28), and CX 3 CR1 (homing to stressed endothelium) (22,(29)(30)(31). CCR7 was not expressed on either population of PB hCMV-specific CD8 ϩ T cells (Fig.…”

Section: Circulating Il-7r␣mentioning

confidence: 99%

Clonal Evolution of CD8⁺T Cell Responses against Latent Viruses: Relationship among Phenotype, Localization, and Function

Remmerswaal

Klarenbeek

Alves

et al. 2015

J Virol

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Human cytomegalovirus (hCMV) infection is characterized by a vast expansion of resting effector-type virus-specific T cells in the circulation. In mice, interleukin-7 receptor ␣ (IL-7R␣)-expressing cells contain the precursors for long-lived antigen-experienced CD8؉ T cells, but it is unclear if similar mechanisms operate to maintain these pools in humans. Here, we studied whether IL-7R␣-expressing cells obtained from peripheral blood (PB) or lymph nodes (LNs) sustain the circulating effector-type hCMVspecific pool. Using flow cytometry and functional assays, we found that the IL-7R␣؉ hCMV-specific T cell population comprises cells that have a memory phenotype and lack effector features. We used next-generation sequencing of the T cell receptor to compare the clonal repertoires of IL-7R␣؉ and IL-7R␣ ؊ subsets. We observed limited overlap of clones between these subsets during acute infection and after 1 year. When we compared the hCMV-specific repertoire between PB and paired LNs, we found many identical clones but also clones that were exclusively found in either compartment. New clones that were found in PB during antigenic recall were only rarely identical to the unique LN clones. Thus, although PB IL-7R␣-expressing and LN hCMV-specific CD8 ؉ T cells show typical traits of memory-type cells, these populations do not seem to contain the precursors for the novel hCMV-specific CD8 ؉ T cell pool during latency or upon antigen recall. IL-7R␣ ؉ PB and LN hCMV-specific memory cells form separate virus-specific compartments, and precursors for these novel PB hCMV-specific CD8 ؉ effector-type T cells are possibly located in other secondary lymphoid tissues or are being recruited from the naive CD8 ؉ T cell pool. IMPORTANCE Insight into the self-renewal properties of long-lived memory CD8؉ T cells and their location is crucial for the development of both passive and active vaccination strategies. Human CMV infection is characterized by a vast expansion of resting effector-type cells. It is, however, not known how this population is maintained. We here investigated two possible compartments for effector-type cell precursors: circulating acute-phase IL-7R␣-expressing hCMV-specific CD8 ؉ T cells and lymph node (LN)-residing hCMV-specific (central) memory cells. We show that new clones that appear after primary hCMV infection or during hCMV reactivation seldom originate from either compartment. Thus, although identical clones may be maintained by either memory population, the precursors of the novel clones are probably located in other (secondary) lymphoid tissues or are recruited from the naive CD8 ؉ T cell pool.

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Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage

Cited by 84 publications

References 40 publications

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Clonal Evolution of CD8⁺T Cell Responses against Latent Viruses: Relationship among Phenotype, Localization, and Function

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Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage

Cited by 84 publications

References 40 publications

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

Cytomegalovirus‐Productive Infection Is Associated With Acute Coronary Syndrome

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Clonal Evolution of CD8+T Cell Responses against Latent Viruses: Relationship among Phenotype, Localization, and Function

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Clonal Evolution of CD8⁺T Cell Responses against Latent Viruses: Relationship among Phenotype, Localization, and Function